ROLE OF IL-17 AND TH17 CELLS IN HSV INDUCED OCULAR IMMUNOPATHOLOGY

Herpes simplex virus (HSV) infection of the cornea leads to a blinding immuno-inflammatory condition of the eye also called stromal keratitis (SK). SK immunopathology is characterized by the infiltration of CD4+ T cells of Th1 phenotype as well as the development of new blood vessels into the normally avascular cornea. Studies in mouse models of SK have firmly established the role of CD4+ T cells, and particularly of Th1 phenotype, as the principal mediators of SK immunopathology. However, with the recent discovery of IL-17A and Th17 cells, the role of this cytokine as well as Th17 cells remains to be further defined. Recently it was shown that the normal cornea expresses VEGF-A, however its biological activity is impeded by its binding to a soluble form of VEGF-A receptor-1 (sVEGFR-1). Past studies have implicated the role of vascular endothelial growth factor-A (VEGF-A) in HSV induced corneal angiogenesis, however the source of VEGF-A as well as molecular mechanisms, particularly in the context of VEGF-A/sVEGFR-1 balance during HSV infection, are poorly understood. The first part of this dissertation (I) reviews past literature on HSV induced corneal SK immunopathology. It focuses on the understanding of HSV-1 induced events that particularly results in corneal angiogenesis as well as tissue damage mediated by different type of cells as well as their secreted products. The next three parts (II-IV) focus on the mechanisms of HSV induced corneal angiogenesis as well as the relative role of Th1 and Th17 cells in SK immunopathology. Results in part II focuses on the relative role of IFN-γ/IL-17 as well as Th1/Th17 cells in HSV induced corneal immunopathology. The third section evaluate the significance of VEGF-A/sVEGFR-1 balance in HSV induced corneal neovascularization. Results in part IV focus on the role of IL-17A in altering the balance between VEGF-A and sVEGFR-1 post ocular HSV infection and subsequent corneal angiogenesis. Collectively these studies identified novel mechanisms by which HSV infection of the cornea leads to the development of angiogenesis as well as corneal tissue damage and subsequent SK immunopathology, the most common cause of infectious blindness in the Western World

An Innovative Approach for Predicting Software Defects by Handling Class Imbalance Problem

From last decade unbalanced data has gained attention as a major challenge for enhancing software quality and reliability. Due to evolution in advanced software development tools and processes, today’s developed software product is much larger and complicated in nature. The software business faces a major issue in maintaining software performance and efficiency as well as cost of handling software issues after deployment of software product. The effectiveness of defect prediction model has been hampered by unbalanced data in terms of data analysis, biased result, model accuracy and decision making. Predicting defects before they affect your software product is one way to cut costs required to maintain software quality. In this study we are proposing model using two level approach for class imbalance problem which will enhance accuracy of prediction model. In the first level, model will balance predictive class at data level by applying sampling method. Second level we will use Random Forest machine learning approach which will create strong classifier for software defect. Hence, we can enhance software defect prediction model accuracy by handling class imbalance issue at data and algorithm level

Clinical profile of dengue patients: A hospital based study

Context: For most of the patients, dengue is a self-limiting viral fever, but in some patients, it results in a life threatening conditioncalled as dengue hemorrhagic fever or dengue shock syndrome. Objective: We attempted to determine the common and atypicalclinical and laboratory features in children suffering from dengue fever, which will help in early diagnosis and management of patientssuffering from dengue infection. Design: Hospital based descriptive, cross-sectional study conducted from January 2014 to December2014. Setting: Tertiary referral teaching hospital. Patients: All patients between 1-month and 12 years admitted in pediatric ward withsymptoms suggestive of dengue and who turn out to be positive for NS1 antigen alone or NS1 and immunoglobulin M antibody againstdengue were included in the study. Data regarding relevant history and clinical examination and outcome and relevant investigationswere collected. Results: Of 250 children included in the study, 145 (58%) were male and 105 (42%) were female. The most commonpresenting complaint was fever (92.8%), followed by abdominal pain (46.4%). The most common clinical sign was pyrexia followedby relative bradycardia (37.6%) and hypotension (26.4%). On laboratory investigation, the most common abnormality detected wasleucopenia (81.6%) followed by thrombocytopenia (69.2%). Conclusion: A high index of suspicion is required on the part of treatingpediatrician to diagnose dengue early and treat accordingly to prevent mortality due to dengue

Controlling Viral Immuno-Inflammatory Lesions by Modulating Aryl Hydrocarbon Receptor Signaling

Ocular herpes simplex virus infection can cause a blinding CD4+ T cell orchestrated immuno-inflammatory lesion in the cornea called Stromal Keratitis (SK). A key to controlling the severity of SK lesions is to suppress the activity of T cells that orchestrate lesions and enhance the representation of regulatory cells that inhibit effector cell function. In this report we show that a single administration of TCDD (2, 3, 7, 8- Tetrachlorodibenzo-p-dioxin), a non-physiological ligand for the AhR receptor, was an effective means of reducing the severity of SK lesions. It acted by causing apoptosis of Foxp3- CD4+ T cells but had no effect on Foxp3+ CD4+ Tregs. TCDD also decreased the proliferation of Foxp3- CD4+ T cells. The consequence was an increase in the ratio of Tregs to T effectors which likely accounted for the reduced inflammatory responses. In addition, in vitro studies revealed that TCDD addition to anti-CD3/CD28 stimulated naïve CD4+ T cells caused a significant induction of Tregs, but inhibited the differentiation of Th1 and Th17 cells. Since a single TCDD administration given after the disease process had been initiated generated long lasting anti-inflammatory effects, the approach holds promise as a therapeutic means of controlling virus induced inflammatory lesions

Galectin-9/TIM-3 Interaction Regulates Virus-Specific Primary and Memory CD8+ T Cell Response

In this communication, we demonstrate that galectin (Gal)-9 acts to constrain CD8+ T cell immunity to Herpes Simplex Virus (HSV) infection. In support of this, we show that animals unable to produce Gal-9, because of gene knockout, develop acute and memory responses to HSV that are of greater magnitude and better quality than those that occur in normal infected animals. Interestingly, infusion of normal infected mice with α-lactose, the sugar that binds to the carbohydrate-binding domain of Gal-9 limiting its engagement of T cell immunoglobulin and mucin (TIM-3) receptors, also caused a more elevated and higher quality CD8+ T cell response to HSV particularly in the acute phase. Such sugar treated infected mice also had expanded populations of effector as well as memory CD8+ T cells. The increased effector T cell responses led to significantly more efficient virus control. The mechanisms responsible for the outcome of the Gal-9/TIM-3 interaction in normal infected mice involved direct inhibitory effects on TIM-3+ CD8+ T effector cells as well as the promotion of Foxp3+ regulatory T cell activity. Our results indicate that manipulating galectin signals, as can be achieved using appropriate sugars, may represent a convenient and inexpensive approach to enhance acute and memory responses to a virus infection

Modulation of Inflammatory Responses by Wnt/β-catenin Signaling in Dendritic cells: A Novel Immunotherapy target for auto-immunity and Cancer

The Wnt/β-catenin pathway is an evolutionarily conserved signaling pathway critical for several biological processes. An aberrant Wnt/β-catenin signaling is linked to several human diseases. Emerging studies have highlighted the regulatory role of the Wnt/β-catenin signaling pathway in normal physiological processes of parenchymal and hematopoietic cells. Recent studies have shown that the activation of Wnt/β-catenin pathway in dendritic cells (DCs) play a critical role in mucosal tolerance and suppression of chronic auto-immune pathologies. Alternatively, tumors activate Wnt/β-catenin pathway in DCs to induce immune tolerance and thereby evade anti-tumor immunity through suppression of effector T cell responses and promotion of regulatory T cell responses. Here, we review our work and current understanding of how Wnt/β-catenin signaling in DCs shapes the immune response in cancer and autoimmunity and discuss how Wnt/β -catenin pathway can be targeted for successful therapeutic interventions in various human diseases

A novel acrylic monomer containing 1,2,3-Triazole: Synthesized, characterized, and tested for antibacterial activity

Antibacterial, antifungal, hypoglycemic, antihypertensive, analgesic, anti-inflammatory, anti-tumor, anti-viral, urease inhibition, and many more pharmacological effects are related with the 1,2,4-triazole nucleus. Authors created a new series of 4-Amino-5-substituted-3,4-dihydro-2H-[1,2,4]triazole-3-thiols in response to the growing importance of 1,2,4-triazoles as powerful physiologically active agents. Two distinct 2- (5- Mercapto-3-subsituted-1,5-dihydro-[1,2,4]triazol-4-yl) various Schiff bases and -isoindole-1,3-dione(6a-6e) 4-[(4-Dimethylamino-benzylidene)-amino] is a 4-[(4-Dimethylamino-benzylidene)-amino] -5-subsituted-3,4-dihydro-2H-[1,2,4] Different 4-Amino-5-substituted-3,4-dihydro-2H-[1,2,4]triazole-3-thiols were produced and analyzed utilizing spectral techniques such as 1H NMR, 13C NMR, FTIR, and mass spectrometry. Antimicrobial activity against Gram Positive, Gram Negative, and fungal stains was tested on all of these substances. The majority of these compounds have strong antibacterial properties. P. aeruginosa, E. coli, B. subtilis, and B. cerus are all susceptible to compound 6a, 6b, 7c, and 7a. Compounds 7d and 7e were discovered to be effective against P. areuginosa. The typical drugs were Ciprofloxacin and Fluconazole

Therapeutic administration of TCDD diminishes SK severity.

<p>C57BL/6 animals infected with 1×10⁴ PFU of HSV were given either TCDD or vehicle IP on day 5 pi. The disease progression was analyzed throughout time. A, The progression of SK lesion severity was significantly reduced in the group of mice treated with TCDD as compared with control mice. Kinetics of SK severity is shown. B, Individual eye SK scores on day 10, 12 and 15 pi. C, The progression of angiogenesis was significantly reduced in the group of mice treated with TCDD as compared with control mice. Kinetics of angiogenesis lesion severity is shown. D, Individual eye angiogenesis scores on day 10, 12 and 15 pi. E, Eyes were processed for cryo-sections on day 15 pi. Hematoxylin and eosin staining was carried out on 6-μm sections and pictures were taken at different microscope augmentations. F, The progression of SK lesion severity was significantly reduced in the group of mice treated with TCDD as compared with control mice. Kinetics of SK severity is shown up to day 28 pi. Data are representative of 3 independent experiments and show mean values ± SEM (n = 14 mice/group). <i>P</i>≤0.001(***), <i>P</i>≤0.01(**), <i>P</i>≤0.05(*).</p